tbuckley/cabot-search huggingface dataset:
Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets
Authors: Vladimir Laletin, Pierre-Louis Bernard, Cathy Costa da Silva, Geoffrey Guittard, Jacques A Nunes
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immunotherapy strategies aim to mobilize immune defenses against tumor cells by targeting mainly T cells. Co-inhibitory receptors or immune checkpoints (ICPs) (such as PD-1 and CTLA4) can limit T cell receptor (TCR) signal propagation in T cells. Antibody-based blocking of immune checkpoints (immune checkpoint inhibitors, ICIs) enable escape from ICP inhibition of TCR signaling. ICI therapies have significantly impacted the prognosis and survival of patients with cancer. However, many patients remain refractory to these treatments. Thus, alternative approaches for cancer immunotherapy are needed. In addition to membrane-associated inhibitory molecules, a growing number of intracellular molecules may also serve to downregulate signaling cascades triggered by TCR engagement. These molecules are known as intracellular immune checkpoints (iICPs). Blocking the expression or the activity of these intracellular negative signaling molecules is a novel field of action to boost T cell-mediated antitumor responses. This area is rapidly expanding. Indeed, more than 30 different potential iICPs have been identified. Over the past 5 years, several phase I/II clinical trials targeting iICPs in T cells have been registered. In this study, we summarize recent preclinical and clinical data demonstrating that immunotherapies targeting T cell iICPs can mediate regression of solid tumors including (membrane associated) immune-checkpoint inhibitor refractory cancers. Finally, we discuss how these iICPs are targeted and controlled. Thereby, iICP inhibition is a promising strategy opening new avenues for future cancer immunotherapy treatments.
An open-label multiyear study of sargramostim-treated Parkinson’s disease patients examining drug safety, tolerability, and immune biomarkers from limited case numbers
Authors: Katherine E. Olson, Mai M. Abdelmoaty, Krista L. Namminga, Yaman Lu, Helen Obaro, Pamela Santamaria, R. Lee Mosley, Howard E. Gendelman
Journal: Translational Neurodegeneration (2023)

The clinical utility and safety of sargramostim has previously been reported in cancer, acute radiation syndrome, autoimmune disease, inflammatory conditions, and Alzheimer's disease. The safety, tolerability, and mechanisms of action in Parkinson's disease (PD) during extended use has not been evaluated. As a primary goal, safety and tolerability was assessed in five PD patients treated with sargramostim (Leukine®, granulocyte-macrophage colony-stimulating factor) for 33 months. Secondary goals included numbers of CD4+ T cells and monocytes and motor functions. Hematologic, metabolic, immune, and neurological evaluations were assessed during a 5-day on, 2-day off therapeutic regimen given at 3 μg/kg. After 2 years, drug use was discontinued for 3 months. This was then followed by an additional 6 months of treatment. Sargramostim-associated adverse events included injection-site reactions, elevated total white cell counts, and bone pain. On drug, blood analyses and metabolic panels revealed no untoward side effects linked to long-term treatment. Unified Parkinson's Disease Rating Scale scores remained stable throughout the study while regulatory T cell number and function were increased. In the initial 6 months of treatment, transcriptomic and proteomic monocyte tests demonstrated autophagy and sirtuin signaling. This finding paralleled anti-inflammatory and antioxidant activities within both the adaptive and innate immune profile arms. Taken together, the data affirmed long-term safety as well as immune and anti-inflammatory responses reflecting clinical stability in PD under the sargramostim treatment. Confirmation in larger patient populations is planned in a future phase II evaluation. ClinicalTrials.gov: NCT03790670, Date of Registration: 01/02/2019, URL: https://clinicaltrials.gov/ct2/show/NCT03790670?cond=leukine+parkinson%27s&draw=2&rank=2 .
Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling
Authors: Elena Kotsiliti, Valentina Leone, Svenja Schuehle, Olivier Govaere, Hai Li, Monika J. Wolf, Helena Horvatic, Sandra Bierwirth, Jana Hundertmark, Donato Inverso, Laimdota Zizmare, Avital Sarusi-Portuguez, Revant Gupta, Tracy O’Connor, Anastasios D. Giannou, Ahmad Mustafa Shiri, Yehuda Schlesinger, Maria Garcia Beccaria, Charlotte Rennert, Dominik Pfister, Rupert Öllinger, Iana Gadjalova, Pierluigi Ramadori, Mohammad Rahbari, Nuh Rahbari, Marc E. Healy, Mirian Fernández-Vaquero, Neda Yahoo, Jakob Janzen, Indrabahadur Singh, Chaofan Fan, Xinyuan Liu, Monika Rau, Martin Feuchtenberger, Eva Schwaneck, Sebastian J. Wallace, Simon Cockell, John Wilson-Kanamori, Prakash Ramachandran, Celia Kho, Timothy J. Kendall, Anne-Laure Leblond, Selina J. Keppler, Piotr Bielecki, Katja Steiger, Maike Hofmann, Karsten Rippe, Horst Zitzelsberger, Achim Weber, Nisar Malek, Tom Luedde, Mihael Vucur, Hellmut G. Augustin, Richard Flavell, Oren Parnas, Roland Rad, Olivier Pabst, Neil C. Henderson, Samuel Huber, Andrew Macpherson, Percy Knolle, Manfred Claassen, Andreas Geier, Christoph Trautwein, Kristian Unger, Eran Elinav, Ari Waisman, Zeinab Abdullah, Dirk Haller, Frank Tacke, Quentin M. Anstee, Mathias Heikenwalder
Journal: Journal of Hepatology (2023)

The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.
Relative Effects of Splenic and Bone-Marrow Cells on Lethally Irradiated Mice
Authors: Takashi Makinodan, Nazareth Gengozian, Isabel C. Shekarchi
Journal: JNCI Journal of the National Cancer Institute (1958)

Journal Article Relative Effects of Splenic and Bone-Marrow Cells on Lethally Irradiated Mice Get access Takashi Makinodan, Takashi Makinodan Biology Division, Oak Ridge National Laboratory,3Oak Ridge, Tennessee Search for other works by this author on: Oxford Academic PubMed Google Scholar Nazareth Gengozian, Nazareth Gengozian Biology Division, Oak Ridge National Laboratory,3Oak Ridge, Tennessee Search for other works by this author on: Oxford Academic PubMed Google Scholar Isabel C. Shekarchi Isabel C. Shekarchi Biology Division, Oak Ridge National Laboratory,3Oak Ridge, Tennessee Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 20, Issue 3, March 1958, Pages 591–600, https://doi.org/10.1093/jnci/20.3.591 Published: 01 March 1958 Article history Received: 20 September 1957 Published: 01 March 1958
Isolation of gene markers of differentiated and proliferating vascular smooth muscle cells.
Authors: C M Shanahan, P L Weissberg, J C Metcalfe
Journal: Circulation Research (1993)

To isolate specific markers of both differentiated and proliferating vascular smooth muscle cells (VSMCs), we used the technique of differential cDNA screening using RNA from cultured rat aortic VSMCs. The tissue specificity of expression of all of the cDNAs isolated was determined by Northern analysis. We isolated seven distinct cDNAs that were more strongly expressed in freshly dispersed, differentiated, aortic VSMCs compared with dedifferentiated late-passage cells. These were the cDNAs for tropoelastin, a matrix protein; alpha-smooth muscle (SM) actin, gamma-SM actin, calponin, and phospholamban, which are all proteins associated with the contractile function of differentiated VSMCs; SM22 alpha, a smooth muscle-specific protein of unknown function, and CHIP28, a putative membrane channel protein that is not highly expressed in other SM tissues and may therefore be a new VSMC marker. Two cDNAs that were expressed preferentially in late-passage dedifferentiated VSMCs were also isolated. These were the cDNAs for osteopontin and matrix Gla protein (MGP). Like CHIP28, MGP was strongly expressed in aortic VSMCs but not in other types of tissues containing SM cells, suggesting that both have specific functions in vascular tissue. Osteopontin and MGP have both previously been isolated from developing bone. Their expression in proliferating VSMCs suggests that they may be involved in regulating the calcification that commonly occurs in vascular lesions. The set of cDNAs obtained extends the range of DNA probes that are available for identifying VSMCs and characterizing their phenotype in vivo by in situ hybridization. Therefore, they should aid in the analysis of gene expression during the development of vessel lesions.
Abstract #5600: 90Y-carrying liposome as a promising agent for systemic radionuclide therapy: Efficient encapsulation of 90Y in liposome, biodistribution and SPECT/CT imaging, and therapeutic efficancy
Authors: Izumi Umeda, Masamitsu Kobayashi, Kazumasa Inoue, Masayuki Yamaguchi, Hiroshi Yamaguchi, Hiroshi Kosano, Hirofumi Fujii
Journal: Cancer Research (2009)

Objectives: Liposomes including particle-emitting radionuclides, such as 186/188Re and 90Y, are very attractive carriers for radionuclide therapy because they can effectively deliver radionuclides to tumors with high target-to-background ratio. The difficulty of encapsulating sufficient amount of radionuclides in liposomes is, however, interfering with their therapeutic applications. In this study, we proposed a method to effectively encapsulate 90Y in liposomes, investigated their tissue distributions including SPECT/CT imaging with 111In-liposomes, and evaluated its therapeutic effect. Methods: Liposomes were composed of DSPC and cholesterol (molar ratio of 2:1) and they were sized to approximately 100 nm in diameter. 90Y was encapsulated into liposomes by the following method, by which we have already successfully encapsulated 111In and 67Ga into liposomes effectively. First, 90Y was transported to the inner liposomal aqueous compartment through liposomal lipid membrane by means of a lipophilic chelating ligand. Then, 90Y was transferred to pre-included hydrophilic chelating ligands with stronger affinity to 90Y than lipophilic ligands. Various combinations of lipophilic and hydrophilic chelators were examined for the optimal encapsulation. The tissue distribution of liposomes were imaged by a SPECT/CT scanner and their therapeutic effects were studied using Colon 26-bearing BALB/c mice. Results: The reactivity of 90Y to chelators was quite different from that of 111In or 67Ga, and the combination of tropolone and DOTA was optimal for 90Y. Although the concentration balance of two chelating agents, reaction temperature and liposomal lipid concentration markedly affected the encapsulating efficiency, 90Y could be encapsulated in the liposomes with over 90% efficiency under the optimal condition, and 90Y of 2 MBq (80 MBq/kg) could be successfully injected into a mouse. Studies on the tissue distribution revealed high tumor uptake (15.2 % of administered dose(AD)/ g of tumor at 24 h after the injection) and good tumor-to-normal tissue ratios, showing notably very low accumulation in bone marrow (  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5600.
AMG 145, a Monoclonal Antibody Against PCSK9, Facilitates Achievement of National Cholesterol Education Program–Adult Treatment Panel III Low-Density Lipoprotein Cholesterol Goals Among High-Risk Patients
Authors: Nihar R. Desai, Robert P. Giugliano, Jing Zhou, Payal Kohli, Ransi Somaratne, Elaine Hoffman, Thomas Liu, Robert Scott, Scott M. Wasserman, Marc S. Sabatine
Journal: Journal of the American College of Cardiology (2013)
Evaluation of FLT-PET as early predictor of response to radical RT in patient with non-small cell lung cancer.
Authors: I Trigonis, P Koh, Marie-Claude Asselin, M Tamal, B Taylor, T Goldstone, E Dean, O Ataman, A Jackson, Corinne Faivre-Finn, Fiona Blackhall
Journal: Journal of Thoracic Oncology (2011)
MegaPro, a clinically translatable nanoparticle for <i>in vivo</i> tracking of stem cell implants in pig cartilage defects
Authors: Vidyani Suryadevara, Mohammad Javad Hajipour, Lisa C. Adams, Nour Mary Aissaoui, Ali Rashidi, Louise Kiru, Ashok J. Theruvath, Ching‐Hsin Huang, Masahiro Maruyama, Masanori Tsubosaka, Jennifer K. Lyons, Wei (Emma) Wu, Raheleh Roudi, Stuart B. Goodman, Heike E. Daldrup‐Link
Journal: Theranostics (2023)

Rationale: Efficient labeling methods for mesenchymal stem cells (MSCs) are crucial for tracking and understanding their behavior in regenerative medicine applications, particularly in cartilage defects.MegaPro nanoparticles have emerged as a potential alternative to ferumoxytol nanoparticles for this purpose.Methods: In this study, we employed mechanoporation to develop an efficient labeling method for MSCs using MegaPro nanoparticles and compared their effectiveness with ferumoxytol nanoparticles in tracking MSCs and chondrogenic pellets.Pig MSCs were labeled with both nanoparticles using a custom-made microfluidic device, and their characteristics were analyzed using various imaging and spectroscopy techniques.The viability and differentiation capacity of labeled MSCs were also assessed.Labeled MSCs and chondrogenic pellets were implanted into pig knee joints and monitored using MRI and histological analysis.Results: MegaPro-labeled MSCs demonstrated shorter T2 relaxation times, higher iron content, and greater nanoparticle uptake compared to ferumoxytol-labeled MSCs, without significantly affecting their viability and differentiation capacity.Post-implantation, MegaPro-labeled MSCs and chondrogenic pellets displayed a strong hypointense signal on MRI with considerably shorter T2* relaxation times compared to adjacent cartilage.The hypointense signal of both MegaPro-and ferumoxytol-labeled chondrogenic pellets decreased over time.Histological evaluations showed regenerated defect areas and proteoglycan formation with no significant differences between the labeled groups. Conclusion:Our study demonstrates that mechanoporation with MegaPro nanoparticles enables efficient MSC labeling without affecting viability or differentiation.MegaPro-labeled cells show enhanced MRI tracking compared to ferumoxytol-labeled cells, emphasizing their potential in clinical stem cell therapies for cartilage defects.
Translaryngeal Resistance: A Measurement to Assist Decision Making in Upper Airway Pathology
Authors: Zoe Fretheim-Kelly, Hege Synnøve Havstad Clemm, Ola Drange Røksund, Magnus Hilland, Maria Vollsæter, Thomas Halvorsen
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Translaryngeal Resistance: A Measurement to Assist Decision Making in Upper Airway Pathology." American Journal of Respiratory and Critical Care Medicine, 208(6), pp. e32–e34
Prediabetes and Fracture Risk Among Midlife Women in the Study of Women’s Health Across the Nation
Authors: Albert Shieh, Gail A. Greendale, Jane A. Cauley, Carrie A. Karvonen-Gutierrez, Arun S. Karlamangla
Journal: JAMA Network Open (2023)

Importance Whether prediabetes is associated with fracture is uncertain. Objective To evaluate whether prediabetes before the menopause transition (MT) is associated with incident fracture during and after the MT. Design, Setting, and Participants This cohort study used data collected between January 6, 1996, and February 28, 2018, in the Study of Women’s Health Across the Nation cohort study, an ongoing, US-based, multicenter, longitudinal study of the MT in diverse ambulatory women. The study included 1690 midlife women in premenopause or early perimenopause at study inception (who have since transitioned to postmenopause) who did not have type 2 diabetes before the MT and who did not take bone-beneficial medications before the MT. Start of the MT was defined as the first visit in late perimenopause (or first postmenopausal visit if participants transitioned directly from premenopause or early perimenopause to postmenopause). Mean (SD) follow-up was 12 (6) years. Statistical analysis was conducted from January to May 2022. Exposure Proportion of visits before the MT that women had prediabetes (fasting glucose, 100-125 mg/dL [to convert to millimoles per liter, multiply by 0.0555]), with values ranging from 0 (prediabetes at no visits) to 1 (prediabetes at all visits). Main Outcomes and Measures Time to first fracture after the start of the MT, with censoring at first diagnosis of type 2 diabetes, initiation of bone-beneficial medication, or last follow-up. Cox proportional hazards regression was used to examine the association (before and after adjustment for bone mineral density) of prediabetes before the MT with fracture during the MT and after menopause. Results This analysis included 1690 women (mean [SD] age, 49.7 [3.1] years; 437 Black women [25.9%], 197 Chinese women [11.7%], 215 Japanese women [12.7%], and 841 White women [49.8%]; mean [SD] body mass index [BMI] at the start of the MT, 27.6 [6.6]). A total of 225 women (13.3%) had prediabetes at 1 or more study visits before the MT, and 1465 women (86.7%) did not have prediabetes before the MT. Of the 225 women with prediabetes, 25 (11.1%) sustained a fracture, while 111 of the 1465 women without prediabetes (7.6%) sustained a fracture. After adjustment for age, BMI, and cigarette use at the start of the MT; fracture before the MT; use of bone-detrimental medications; race and ethnicity; and study site, prediabetes before the MT was associated with more subsequent fractures (hazard ratio for fracture with prediabetes at all vs no pre-MT visits, 2.20 [95% CI, 1.11-4.37]; P = .02). This association was essentially unchanged after controlling for BMD at the start of the MT. Conclusions and Relevance This cohort study of midlife women suggests that prediabetes was associated with risk of fracture. Future research should determine whether treating prediabetes reduces fracture risk.
MOF-derived bimetallic nanozyme to catalyze ROS scavenging for protection of myocardial injury
Authors: Kaiyan Xiang, Haoguang Wu, Yu Liu, Sheng Wang, Xueling Li, Bowei Yang, Yunming Zhang, Long Ma, Guangming Lu, Liangcan He, Qianqian Ni, Longjiang Zhang
Journal: Theranostics (2023)

Rationale: Myocardial injury triggers intense oxidative stress, inflammatory response, and cytokine release, which are essential for myocardial repair and remodeling.Excess reactive oxygen species (ROS) scavenging and inflammation elimination have long been considered to reverse myocardial injuries.However, the efficacy of traditional treatments (antioxidant, anti-inflammatory drugs and natural enzymes) is still poor due to their intrinsic defects such as unfavorable pharmacokinetics and bioavailability, low biological stability, and potential side effects.Nanozyme represents a candidate to effectively modulate redox homeostasis for the treatment of ROS related inflammation diseases.Methods: We develop an integrated bimetallic nanozyme derived from metal-organic framework (MOF) to eliminate ROS and alleviate inflammation.The bimetallic nanozyme (Cu-TCPP-Mn) is synthesized by embedding manganese and copper into the porphyrin followed by sonication, which could mimic the cascade activities of superoxide dismutase (SOD) and catalase (CAT) to transform oxygen radicals to hydrogen peroxide, followed by the catalysis of hydrogen peroxide into oxygen and water.Enzyme kinetic analysis and oxygen-production velocities analysis were performed to evaluate the enzymatic activities of Cu-TCPP-Mn.We also established myocardial infarction (MI) and myocardial ischemia-reperfusion (I/R) injury animal models to verify the ROS scavenging and anti-inflammation effect of Cu-TCPP-Mn.Results: As demonstrated by kinetic analysis and oxygen-production velocities analysis, Cu-TCPP-Mn nanozyme possesses good performance in both SOD-and CAT-like activities to achieve synergistic ROS scavenging effect and provide protection for myocardial injury.In both MI and I/R injury animal models, this bimetallic nanozyme represents a promising and reliable technology to protect the heart tissue from oxidative stress and inflammation-induced injury, and enables the myocardial function to recover from otherwise severe damage.Conclusions: This research provides a facile and applicable method to develop a bimetallic MOF nanozyme, which represents a promising alternative to the treatment of myocardial injuries.
PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING–Type I Interferon Signaling in Glioblastoma
Authors: Isha Mondal, Oishika Das, Raymond Sun, Jian Gao, Bohyeon Yu, Aaron Diaz, Jinan Behnan, Abhishek Dubey, Zhipeng Meng, Emad Eskandar, Beisi Xu, Rongze Olivia Lu, Winson S. Ho
Journal: Cancer Research (2023)

Glioblastoma (GBM) is an immunologically "cold" tumor that does not respond to current immunotherapy. Here, we demonstrate a fundamental role for the α-isoform of the catalytic subunit of protein phosphatase-2A (PP2Ac) in regulating glioma immunogenicity. Genetic ablation of PP2Ac in glioma cells enhanced double-stranded DNA (dsDNA) production and cGAS-type I IFN signaling, MHC-I expression, and tumor mutational burden. In coculture experiments, PP2Ac deficiency in glioma cells promoted dendritic cell (DC) cross-presentation and clonal expansion of CD8+ T cells. In vivo, PP2Ac depletion sensitized tumors to immune-checkpoint blockade and radiotherapy treatment. Single-cell analysis demonstrated that PP2Ac deficiency increased CD8+ T-cell, natural killer cell, and DC accumulation and reduced immunosuppressive tumor-associated macrophages. Furthermore, loss of PP2Ac increased IFN signaling in myeloid and tumor cells and reduced expression of a tumor gene signature associated with worse patient survival in The Cancer Genome Atlas. Collectively, this study establishes a novel role for PP2Ac in inhibiting dsDNA-cGAS-STING signaling to suppress antitumor immunity in glioma.
High‐Throughput Bioprinting of Geometrically‐Controlled Pre‐Vascularized Injectable Microgels for Accelerated Tissue Regeneration
Authors: Cristiane M. Franca, Avathamsa Athirasala, Ramesh Subbiah, Anthony Tahayeri, Prakash Selvakumar, Amin Mansoorifar, Sivaporn Horsophonphong, Ashley Sercia, Lina Nih, Luiz E. Bertassoni
Journal: Advanced Healthcare Materials (2023)

Successful integration of cell-laden tissue constructs with host vasculature depends on the presence of functional capillaries to provide oxygen and nutrients to the embedded cells. However, diffusion limitations of cell-laden biomaterials challenge regeneration of large tissue defects that require bulk-delivery of hydrogels and cells. Herein, a strategy to bioprint geometrically controlled, endothelial and stem-cell laden microgels in high-throughput is introduced, allowing these cells to form mature and functional pericyte-supported vascular capillaries in vitro, and then injecting these pre-vascularized constructs minimally invasively in-vivo. It is demonstrated that this approach offers both desired scalability for translational applications as well as unprecedented levels of control over multiple microgel parameters to design spatially-tailored microenvironments for better scaffold functionality and vasculature formation. As a proof-of-concept, the regenerative capacity of the bioprinted pre-vascularized microgels is compared with that of cell-laden monolithic hydrogels of the same cellular and matrix composition in hard-to-heal defects in vivo. The results demonstrate that the bioprinted microgels have faster and higher connective tissue formation, more vessels per area, and widespread presence of functional chimeric (human and murine) vascular capillaries across regenerated sites. The proposed strategy, therefore, addresses a significant issue in regenerative medicine, demonstrating a superior potential to facilitate translational regenerative efforts.